Immunologists have long believed in the power of the immune system to specifically target neoplastic cells, however, only in the last decade has it become clear that i) the immune system recognizes cancer-specific antigens and eliminate tumors, ii) tumors resist immune surveillance, and iii) engaging tumor-specific immunity is likely to become a key component of effective cancer therapies. Naturally or spontaneously immunogenic, leukocyte-infiltrated tumors display the distinctive molecular signatures signifying activation of the innate immune response, which shapes mature, active cancer surveillance by the immune system. Efforts to boost innate anti-tumor responses for cancer immunotherapy primarily focus on dendritic cells and macrophages, considered to be principal effectors of innate immunity. However, preliminary data from our laboratory demonstrates that vascular endothelial cells (vECs) mount remarkably potent innate immune responses by taking up and responding to immuno-stimulatory, cell-free DNA, which is well in accordance with their role as sentinels of the blood. Despite an increasingly accepted appreciation for vECs as bona fide innate effector cells during microbial infections, little is known about how innate anti-tumor responses are engaged in vECs, how innate responses of normal endothelium compare with tumor-derived endothelium, and what is the contribution of innate endothelial responses to the inflammatory landscape of the tumor microenvironment. Our hypothesis asserts that the innate responses of vECs to tumor-derived DNA are suppressed by the tumor microenvironment. Nonetheless, tumor-derived vECs represent a potentially untapped and rich source of innate effectors for cancer immune surveillance. The previously unexplored and highly innovative idea of examining endothelial innate immunity as a novel target for cancer immunotherapy will be investigated using endothelial-tumor cell co-cultures, RNA-sequencing, RNAi/CRISPR-mediated gene deletion, animal models of cancer and human lung tumor biosamples. This proposal leverages diverse skills and expertise focused on understanding endothelial innate immune signaling and its role in cancer immune surveillance. It brings together the principle investigator Dr. Sonia Sharma, a female early stage investigator with an established record of high impact observations in the fields of innate immunity, signal transduction in immune cells, cellular Ca2+ signaling and high throughput RNAi or CRISPR/Cas9-based genomic approaches, with key collaborators with expertise in bio-statistics/informatics, animal models of cancer and human lung tumor biosamples.